EB - Risk factors of metal health disorders II

Question 1

What are some environmental risk factors for mental health disorders? (8)

Answer 1

• Physical health challenges (Gut-brain axis).
• Social and economic stressors (e.g., deprivation, inequality, crime, pollution).
• Early life experiences (e.g., prenatal exposures, adversity, bullying).
• Infections & obstetric complications
• Substance use & abuse.
• Natural disasters.

^Trigger stress responses
Others:

• Infection
• Microbiota-gut-brain axis

Question 2

What 2 CNS disorders require environmental exposure for diagnosis?

Answer 2

• PTSD.
• Substance use disorder

Question 3

What is a transdiagnostic factor?

Answer 3

A psychological process or mechanism that cuts across different mental health disorders. It’s a common thread that links seemingly disparate conditions.

Question 4

How does stress act as a transdiagnostic factor in mental health? (5)

Answer 4

• Cuts across anxiety, mood, and trauma-related disorders.
• Maladaptive responses to stress are central to the development of these disorders.
• Supports the ‘Diathesis-Stress Hypothesis’ - A combination of genetic predisposition and adversity leads to psychopathology.
• Allostatic load - cumulative life stress increases vulnerability
• Critical periods of development - When stress has disproportionate effects leading to long-lasting effects on mental health

Question 5

What is early life stress/adversity? (2)

Answer 5

• A Critical period for brain development
• When the brain highly sensitive to adverse experiences in early life

Question 6

What are the two domains of early life stress (ELA)?

Answer 6

Deprivation: Includes neglect, poverty, and institutionalization.

Threat: Includes sexual, emotional, physical abuse, war, and natural disasters.

Question 7

How does early life stress (ELA) affect mental health? (9)

Answer 7

• Increases risk of:
  Cognitive impairments.
  Substance use disorders.
  Depression disorders
  Anxiety disorders
  Schizophrenia
  Suicide risk
• Predictor of:
  Recurrent episodes
  Severity
  Resistance to treatment.

Question 8

How are rodent models used to study early life stress? (3)

Answer 8

Analyse effects of:

• Natural variations in maternal care.
• Maternal separation.
• Limited bedding and nesting environments.

Question 9

How are Non-human primate models used to study early life stress? (2)

Answer 9

Analyse effects of:

• Natural variations in maternal care
• Variable foraging demand (e.g., inconsistent availability of food resources).

Question 10

What do rodent and non-human primate models have an effect on? (4)

Answer 10

• Brain wiring
• Epigenetics
• Gut-brain axis
• Metabolic changes

Question 11

How does early life adversity (ELA) impact inhibitory interneurons? (2)

Answer 11

• ELA causes shifts in the timing of inhibitory interneuron processes, occurring slightly earlier than in normal development.
• This disruption affects critical periods of brain plasticity, potentially leading to imbalances in excitation and inhibition in the brain.

Question 12

How does early life adversity (ELA) affect serotonergic input? (2)

Answer 12

• ELA reduces serotonergic (5-HT) input during development.
• Lower serotonin signaling increases susceptibility to anxiety and depression later in life.

Question 13

Which brain regions are affected by early life adversity (ELA)? (4)

Answer 13

• Prefrontal Cortex (PFC): Impaired cognition, increased anxiety/depression.
• Hippocampus: Impaired memory, increased anxiety/depression.
• Amygdala: Altered fear behavior, increased anxiety/depression, reduced input from mPFC
• Hypothalamic-pituitary-adrenal (HPA Axis): Impaired stress response.
• Raphe nuclei: increased anxiety/depression

Question 14

What are some cellular changes caused by ELA? (6)

Answer 14

• Synaptic pruning: Disrupted, leading to less refined connections.
• Microglia function: Dysregulated activation affects brain immunity.
• Dendritic branching: Impaired development reduces neuronal complexity.
• Myelination: Slower communication between neurons.
• Neurogenesis: Reduced, especially in the hippocampus.
• GR function: Impaired glucocorticoid receptor response increases stress vulnerability.

Question 15

What is the function of the (HPA) axis? (4)

Answer 15

• The HPA axis regulates homeostatic mechanisms by responding to stress:

1. Hypothalamus (PVN): Releases CRH (corticotropin-releasing hormone).
2. Anterior Pituitary: CRH stimulates the secretion of ACTH into systemic circulation.
3. Adrenal Cortex: ACTH promotes synthesis and release of glucocorticoids.

Question 16

How do glucocorticoids exert their effects in the body? (2)

Answer 16

1. Glucocorticoids bind to their receptors (MRs and GRs) in various organs, including the brain.
2. Once bound, these receptors translocate to the nucleus, causing changes in gene transcription and protein translation.

Question 17

How is the HPA axis dysregulated by early life stress (ELS)? (3)

Answer 17

• Reduced GR expression impairs feedback, increasing stress reactivity.
• ELS resets the HPA axis, leading to heightened stress responses in adulthood.
• Evidence: Rat models show that low maternal care increases corticosterone levels and stress response.

Question 18

What are the epigenetic effects of low maternal care in models? (4)

Answer 18

• Increased DNA methylation at the Nr3c1 gene (encodes GR).
• Reduced histone acetylation, transcription factor binding.
• Decreased GR mRNA and protein expression.
• Effects reversible with HDAC inhibitors, suggesting a potential therapeutic approach.

Question 19

How does ELS affect the reward system?

Answer 19

• Alters gene expression in the Ventral Tegmental Area (VTA).
• ELS combined with adult stress (e.g., STVS) leads to unique transcriptional changes, impacting neuron differentiation, ion transport, and stress resilience.
• ELS combined with STVS significantly increases the latency to eat, indicating heightened stress or anxiety-like behavior

Question 20

How does the immune system influence neurodevelopmental disorders? (3)

Answer 20

• Maternal prenatal infection: Strong risk factor for schizophrenia, autism, ADHD, Tourette syndrome, and BPD.
• Postnatal immune system: Also plays a role in shaping susceptibility to ASD.
• Maternal Immune Activation (MIA) Model: Used to study how immune activation during pregnancy impacts brain development.

Question 21

How does the gut-brain axis influence neuropsychiatric disorders? (3)

Answer 21

• Links diet, gut microbiota, and brain health.
• Specific metabolites like 4EPS (comes from gut flora) can cross the blood-brain barrier and modulate neural networks.
• Example: Elevated 4EPS in ASD correlates with anxiety-like behavior, which can be mitigated using GI-restricted treatments like AB-2004.

Question 22

What are the benefits of targeting the microbiota-gut-brain axis in CNS disorders? (3)

Answer 22

• Early diagnosis and stratification.
• Avoids systemic side effects as treatments don’t need to cross the blood-brain barrier.
• Offers novel therapeutic options for conditions like ASD and anxiety.